The classical receptor for estradiol, ERalpha in addition to its genome-activating properties, is also found within the extracellular membrane where it induces rapid responses to estradiol(E). These receptors are now referred to as membrane ERalpha (mERalpha). It has been demonstrated that E acting extracellularly on mERalpha can rapidly initiate a variety of signal transduction cascades. Brain regions known to be sensitive to the rapid effects of E include the striatum and nucleus accumbens (NAcc). Considerable research has demonstrated that ovarian hormones rapidly activate behavioral and neurochemical indices of dopamine activity in the striatum of female but not male rats. Electrophysiological experiments have shown that E rapidly inhibits the calcium current mediated by L-type calcium channels in medium spiny GABA neurons. Thus, we hypothesize that the enhancement of DA release after E treatment is due to decreased GABA release resulting in a release of inhibition at GABA (B) receptors on presynaptic DA terminals. The experiments proposed will investigate the mechanisms mediating the effects of E in the striatum and nucleus accumbens (NAcc). Specific Aim 1 will test the hypothesis that the enhanced DA release seen after estradiol treatment is due to estradiol, acting on neurons in the striatum to block current mediated by L-type calcium channels. This is hypothesized to produce decreased GABA release and thereby decrease activity at GABA (B) receptors on presynaptic DA terminals. Specific Aim 2 will test the hypothesis that mERa mediates the response to estradiol in the striatum and NAcc. Experiments will use an adeno-associated viral vector (AAV) that expresses the ERa transgene, a transgene that is a dominant negative for the mERalpha, or a control vector to determine whether the behavioral and neurochemical effects of estradiol in the striatum are mediated by mERalpha. The mechanisms through which E acts in the brain and body are important to understand in order to improve our treatment and decrease risks for hormone replacement therapy, breast cancer, and ovarian cancer. It may also be important for our understanding and treatment of a number of neurological disorders including stroke, Alzheimer's disease and Parkinson's disease where estradiol may be neuroprotective.